P54 ORAL ANTIVIRALS RITONAVIR-NIRMATRELVIR AND MOLNUPIRAVIR ARE HIGHLY EFFECTIVE IN PATIENTS WITH MULTIPLE MYELOMA AND COVID-19; A SINGLE-CENTER, PROSPECTIVE STUDY
Authors: V. Spiliopoulou, I. Ntanasis-Stathopoulos, P. Malandrakis, M. Gavriatopoulou, F. Theodorakakou, D. Fotiou, R. E. Syrigou, M. Migkou, M. Roussou, E. Eleutherakis-Papaiakovou, E. Kastritis, M. A Dimopoulos, E. Terpos
Journal: HemaSphere (2023)

Severe SARS-CoV-2 infection is characterized by an initial viral phase, often followed by a severe inflammatory phase. In patients with multiple myeloma (MM), SARS-CoV-2 infection has been associated with severe clinical course and high mortality rates, due to the concomitant disease and treatment-related immunosuppression. Moreover, MM patients do not seem to respond well to vaccination despite adequate immunization, especially those who are on treatment with anti-CD38 or anti-BCMA therapies. Thus, MM patients are at a higher risk for breakthrough infection compared with noncancer patients or patients with solid tumor and supportive treatment with prophylactic use of monoclonal antibodies against SARS-CoV-2 is needed. At the time of COVID-19 infection, the use of antiviral therapy is necessary. Specific antiviral treatment involves viral replication control with monoclonal antibodies and antivirals, including molnupiravir and the ritonavir-boosted nirmatrelvir. Molnupiravir is the prodrug of the ribonucleoside analogue β-D-N4-hydroxycytidine, which inhibits the SARS-CoV-2 replication and reduces viral load. In phase I/II/III studies, it has shown both safety and efficacy, reducing the risk of hospitalization and mortality by approximately 50% in non-hospitalized adults with mild-to-moderate COVID-19 disease who are at risk for poor prognosis. Ritonavir-nirmatrelvir is an oral protease inhibitor that has also reduced the hospitalization and death in clinical trials by approximately 90%. Although available evidence supports the use of antivirals in patients with SARS-CoV-2 infection to prevent severe disease, relevant data on MM patients is scarce. The use of specific antiviral treatment with molnupiravir and ritonavir-boosted nirmatrelvir aims to reduce severe infection and hospitalization in patients with MM, who undergo mild SARS-CoV-2 infection and do not require supplemental oxygen. This prospective study investigates the effect of these two agents on SARS-CoV-2 infection severity and mortality in patients with MM. Patients received either ritonavir-nirmatrelvir or molnupiravir. Consecutive patients with MM and SARS-CoV-2 infection were prospectively enrolled in the study. All patients had microbiologically confirmed SARS-CoV-2 with polymerase chain reaction (PCR). The patients received either ritonavir-nirmatrelvir or molnupiravir according to the national guidelines for five days. Treatment with antivirals was initiated within the first five days from SARS-CoV-2 infection symptoms onset in patients with no need of supplemental oxygen. All patients were at high risk for severe SARS-CoV-2 infection due to the underlying MM. Baseline demographic and clinical characteristics, as well as levels of neutralizing antibodies (NAbs) were collected and compared. The effect of different treatments on SARS-CoV-2 infection severity and mortality was examined. A total of 169 patients infected with SARS-CoV-2 were included. 74 of them were females with an average age of 64.4 years and a mean Body Mass Index (BMI) of 26.91 kg/m2. Regarding their medical history, 14 patients (8.3%) were diagnosed with diabetes mellitus (DM), 71 (42%) had hypertension, six (3.6%) had coronary artery disease (CAD) and 16 (9.5%) had chronic obstructive pulmonary disease (COPD). All patients except for one, were vaccinated, mostly with BioNTech Pfizer vaccine (96.4%). 153 patients had already received 3 doses, seven (7) had received four (4) doses and eight (8) had received two (2) before COVID-19 diagnosis. Regarding treatment, several drug combinations were administered to patients depending on their medical condition and history of MM. These included proteasome inhibitors based regimen, immunomodulatory drugs based regimen, anti-CD38 monoclonal antibody based regimen, anti-BCMA based regimen, and other treatments, such as selinexor and cyclophosphamide. For most of the patients, specifically for 100 of them, this was the 1st line of treatment, for 36 the 2nd, for 16 the 3rd, for 7 the 4th and for 3 patients the 5th line of treatment. As far as the SARS-CoV-2 infection is concerned, 139 patients (82.2%) were treated with ritonavir-nirmatrelvir while the remaining 30 patients (17.8%) with molnupiravir. The duration of antiviral treatment was equal to five (5) days in all but three (3) cases. In total, 149 (88.2%) patients had mild infection, 15 (8.9%) had moderate infection, and five (5) (3%) had a severe one. Severe cases were treated differently, as expected, compared to mild or moderate cases. The special treatment included hospitalization in 6.7% of patients with moderate infection (1 patient) and 100% of patients with severe infection (5 patients), tocilizumab in 5 patients with severe infection, intubation in 2 patients severely infected (40% of patients with severe infection) and corticosteroids in 13 patients with moderate infection (86.7% of these patients) and 5 with a severe one (100% of these patients). An exception was observed regarding use of corticosteroids since it appears that they were given almost equally in patients with moderate and severe outcomes. As far as the antiviral drug type is concerned, no difference in mild, moderate or severe infection was observed (p=0.236). Regarding BMI, age or medical history defined as the presence of DM, COPD, CAD or hypertension no statistically significant difference was observed in the outcome of the infection. Regarding PS, a statistically significant difference of mild versus severe cases was observed (p=0.041), while the difference between mild and moderate cases was borderline non-significant (p=0.052). A difference between severe and mild cases was observed concerning neutralizing antibody response levels before SARS-CoV-2 infection. Patients with severe disease appeared to have lower neutralizing antibody levels before SARS-CoV-2 infection compared to patients with mild disease (p=0.04). The mean and standard deviations for NAbs levels were 67.49%±28.85%, 59%±24.69% and 35.4%±37.57% for the groups of mild, moderate, and severe outcomes respectively. Regarding treatment, despite the various drug types included in the study and their combinations, it was observed that treatment with belantamab mafodotin was significantly related to the outcome. There was a statistically significant higher risk for severe SARS-CoV-2 infection (p<0.001) according to the Fisher’s exact test. In conclusion, the Covid-19 pandemic is a major cause of mortality worldwide and patients with MM are at high risk for severe infection. Unfortunately, the infection cannot be completely controlled, although many antiviral drugs have shown promising therapeutic results. The majority of immunocompromised patients may not be fully protected after vaccination and the use of oral antiviral drugs in case of infection seems to be effective. Ritonavir-nirmatrelvir and molnupiravir seem to be highly effective in preventing severe disease and mortality from SARS-CoV-2 infection in MM patients who are under treatment for the underlying disease. This prospective study indicates the comparable effects of the two treatment options providing an important background for further research.